Chronic wounds associated with diabetes are a burgeoning health problem in the United States. A common characteristic of these poorly healing wounds is a persistent inflammatory response, with accumulation of pro-inflammatory macrophages. The central hypothesis of this proposal is that diabetes induces overproduction of pro-inflammatory monocytes and reduces levels of pro-healing monocytes that each contribute to the poor healing responses in diabetic wounds. We propose a translational study involving both mouse models and human patients with three Specific Aims: in the first Aim, we will determine whether sustained activity of the NLRP3 inflammasome/IL-1? pathway results in overproduction of pro-inflammatory monocytes and impaired healing in diabetes. In the second Aim, we will determine whether impaired activity of Nur77 reduces levels of pro-healing monocytes contributing to impaired healing in diabetes. In the third Aim, we will perform an informative pilot double-blinded, randomized clinical trial to determine whether topical treatment with glyburide can modulate monocyte subsets prior to and/or after wound infiltration and improve healing in diabetes. The proposed experiments will improve knowledge of the role of monocyte subsets during impaired healing in diabetic mice and humans along with cell-intrinsic and cell-extrinsic mechanisms that regulate production of these cells. The impact of these studies lies in the initial translation to a therapy that targets monocyte subsets in diabetic patients to induce resolution of inflammation and stimulate healing responses in hard-to-heal wounds. In addition, the studies could lead to development of assays that involve monitoring blood monocyte subsets as cellular biomarkers to aid in the selection of treatment options for diabetic patients with chronic wounds.